title: Ketamine plus imipramine treatment induces antidepressant-like behavior and increases CREB and BDNF protein levels and PKA and PKC phosphorylation in rat brain.
abstract: A growing body of evidence has pointed to the N-methyl-d-aspartate (NMDA) receptor antagonists as a potential therapeutic target for the treatment of major depression. The present study investigated the possibility of synergistic interactions between antidepressant imipramine with the uncompetitive NMDA receptor antagonist ketamine. Wistar rats were acutely treated with ketamine (5 and 10mg/kg) and imipramine (10 and 20mg/kg) and then subjected to forced swimming tests. The cAMP response element bindig (CREB) and brain-derived neurotrophic factor (BDNF) protein levels and protein kinase C (PKC) and protein kinase A (PKA) phosphorylation were assessed in the prefrontal cortex, hippocampus and amygdala by imunoblot. Imipramine at the dose of 10mg/kg and ketamine at the dose of 5mg/kg did not have effect on the immobility time; however, the effect of imipramine (10 and 20mg/kg) was enhanced by both doses of ketamine. Ketamine and imipramine alone or in combination at all doses tested did not modify locomotor activity. Combined treatment with ketamine and imipramine produced stronger increases of CREB and BDNF protein levels in the prefrontal cortex, hippocampus and amygdala, and PKA phosphorylation in the hippocampus and amygdala and PKC phosphorylation in prefrontal cortex. The results described indicate that co-administration of antidepressant imipramine with ketamine may induce a more pronounced antidepressant activity than treatment with each antidepressant alone. This finding may be of particular importance in the case of drug-resistant patients and could suggest a method of obtaining significant antidepressant actions whilst limiting side effects.
authors.affiliation: Laboratório de Neurociências, Instituto Nacional de Ciência e Tecnologia Translacional em Medicina, Unidade Acadêmica de Ciências da Saúde, Universidade do Extremo Sul Catarinense, 88806-000 Criciúma, SC, Brazil.
authors.forename: Gislaine Z
authors.initials: GZ
authors.lastname: Réus
authors.forename: Roberto B
authors.initials: RB
authors.lastname: Stringari
authors.forename: Karine F
authors.initials: KF
authors.lastname: Ribeiro
authors.forename: Ana K
authors.initials: AK
authors.lastname: Ferraro
authors.forename: Marcelo F
authors.initials: MF
authors.lastname: Vitto
authors.forename: Patrícia
authors.initials: P
authors.lastname: Cesconetto
authors.forename: Claúdio T
authors.initials: CT
authors.lastname: Souza
authors.forename: João
authors.initials: J
authors.lastname: Quevedo
mesh_terms: D000818:Animals; D000928:Antidepressive Agents / Q000008:administration & dosage / Q000494:pharmacology / Q000627:therapeutic use; D001921:Brain / Q000187:drug effects* / Q000378:metabolism; D019208:Brain-Derived Neurotrophic Factor / Q000378:metabolism*; D017362:Cyclic AMP Response Element-Binding Protein / Q000378:metabolism*; D017868:Cyclic AMP-Dependent Protein Kinases / Q000378:metabolism*; D003863:Depression / Q000188:drug therapy* / Q000378:metabolism; D004195:Disease Models, Animal; D004353:Drug Evaluation, Preclinical; D004357:Drug Synergism; D004359:Drug Therapy, Combination; D007099:Imipramine / Q000008:administration & dosage / Q000494:pharmacology / Q000627:therapeutic use*; D046353:Immobility Response, Tonic / Q000187:drug effects; D007649:Ketamine / Q000008:administration & dosage / Q000494:pharmacology / Q000627:therapeutic use*; D009043:Motor Activity / Q000187:drug effects; D010766:Phosphorylation; D011493:Protein Kinase C / Q000378:metabolism*; D051381:Rats; D017208:Rats, Wistar
chemical_list: D000928:Antidepressive Agents; D019208:Brain-Derived Neurotrophic Factor; D017362:Cyclic AMP Response Element-Binding Protein; D007649:Ketamine; D017868:Cyclic AMP-Dependent Protein Kinases; D011493:Protein Kinase C; D007099:Imipramine